Abstract
Post-traumatic stress disorder (PTSD) is more prevalent in women than men, yet much remains to be determined regarding the mechanism underlying this sex difference. Clinical and preclinical studies have shown that low estradiol levels during extinction of fear conditioning in rodents (i.e., cue exposure therapy in humans) leads to poor extinction consolidation and increased fear during extinction recall. The renin–angiotensin system (RAS) is also associated with stress-related pathologies, and RAS antagonists can enhance extinction consolidation in males. However, less is known about how estradiol and the RAS converge to alter fear extinction consolidation in females. Since estradiol downregulates the RAS, we determined the role of surgically (via ovariectomy [OVX]) and pharmacologically (via the hormonal contraceptive [HC], levonorgestrel) clamping estradiol at low levels in female rats on fear-related behavior, serum estradiol and angiotensin II (Ang II) levels, and angiotensin II type I receptor (AT1R) binding in the brain. We then tested whether the AT1R antagonist losartan would alter fear-related behavior in an estradiol-dependent manner. We found that both OVX and HC treatment produced extinction consolidation deficits relative to intact female rats in proestrus (when estradiol levels are high), and that losartan treatment mitigated these deficits and reduced freezing. OVX, but not HC, altered AT1R ligand binding, though HC reduced estradiol and increased Ang II levels in plasma. These findings have significant clinical implications, indicating that administration of an AT1R antagonist, especially if estradiol levels are low, prior to an exposure therapy session may improve treatment outcomes in females.
Highlights
Women are more than twice as likely to be diagnosed with post-traumatic stress disorder (PTSD) compared with men, few studies focus on understanding mechanisms underlying sex differences in its etiology[1,2]
The results of the present experiments suggest that the deficit in extinction consolidation, which is observed in females with surgically or pharmacologically-induced low estradiol levels, can be rescued by systemic treatment with the AT1R antagonist losartan prior to extinction training
No significant differences were found between hormonal contraceptive (HC)- and vehicle-treated females in AT1R ligand binding, levels of the angiotensin II (Ang II) peptide were significantly elevated in HC treated, low estradiol females compared with high estradiol females
Summary
Women are more than twice as likely to be diagnosed with post-traumatic stress disorder (PTSD) compared with men, few studies focus on understanding mechanisms underlying sex differences in its etiology[1,2]. One potential target in understanding how estradiol modulates the consolidation of fear extinction memories is the renin–angiotensin system (RAS), which plays a critical role in modulating sympathetic nervous system tone and cardiovascular health. Drugs that negatively regulate the hypertensive axis of the RAS reduce symptoms of PTSD in human subjects and enhance fear extinction consolidation in males. Estrogen downregulates the hypertensive axis of the RAS, reducing AT1R expression and enzymes involved in the synthesis of angiotensin II (Ang II), the endogenous ligand for the AT1R11–13. Estrogens regulate angiotensin-converting enzyme and AT1R in female rat anterior pituitary, a region involved in the stress response[17]. Though estradiol regulation of the RAS has been extensively studied, it is unclear if this interaction affects the consolidation of fear extinction memories, leaving this as an important and open area of investigation that has clear implications for treatment
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